In order to mount an effective response against an infection, pathogen-specific lymphocytes must first be able to efficiently reach the site of infection. As many pathogens invade and replicate within a specific tissue, the ability to mobilize and target CD8 T cells to an infected tissue is critical for controlling the initial infection. Furthermore, the establishment of a long-lived memory CD8 T cell population within that specific tissue is important for protection against future re-infection. Mounting evidence suggests that individual tissues can regulate the entry of CD8 T cells through the production of specific chemokines and by 'imprinting' the CD8 T cells to express tissue- homing markers. However, the rules that govern CD8 T cell entry and retention to many tissues such as the genital mucosa are unknown. This project will aim to 1) determine the requirements for CD8 T cell entry into different tissues in the context of a localized infection by examining the interaction amongst CD8 T cells, the local tissue microenvironment and other immune cell types and 2) examine the protective immunity provided by tissue-specific vs. recruited memory CD8 T cells after localized challenge. Using a model of herpes simplex virus-2 infection, we will immunize through different routes to generate localized infections and assess the requirement of inflammation and CD4 T cell help for effector CD8 T cell trafficking into different tissues. As the mucosal lining of organs such as the female genital tract stand as major barriers against invading pathogens, we will focus our efforts on understanding the requirements for directing CD8 T cells to the genital mucosa and the ability of long-lived tissue-resident memory CD8 T cells to confer protective immunity. Understanding of the requirements of CD8 T cell migration to individual tissues and their ability to establish memory CD8 T cell populations has important implications for the development of vaccination strategies, notably to infections such as HIV-1, herpes simplex virus and human papillomavirus.